Compounds

ABSTRACT

A compound of formula (I) 
     
       
         
         
             
             
         
       
     
     Or its salts or pharmaceutically acceptable derivatives thereof wherein; 
     A represents a chemical moiety with the general formula (II): 
     
       
         
         
             
             
         
       
     
     X is selected from a group consisting of CH 2 , C(═O), CH(R 5 ), C(R 5 )(R 6 ) or C(R 5 )(R 6 )CH 2 ; 
     R 1  is selected from the group consisting of optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; 
     R 2  is selected from the group consisting of optionally substituted aryl or optionally substituted heteroaryl or NR 7 R 8 ; 
     R 3  R 4  R 5  R 6  R 7  and R 8  are as defined herein; and n=1 or 2 is provided. Pharmaceutical compositions comprising the compounds are also provided. The compounds are useful in treating various conditions including arrhythmia.

FIELD OF THE INVENTION

The present invention relates to compounds of formula (I) which arepotassium channel inhibitors. Compounds in this class may be useful asKv1.3 inhibitors for immunomodulation and the treatment of autoimmune,chronic inflammatory, metabolic diseases and the like. Additionally,compounds in this class may also be useful as Kv1.5 inhibitors for thetreatment or prevention of arrhythmias. Pharmaceutical compositionscomprising the compounds and their use in the treatment of autoimmuneand inflammatory diseases and in the treatment of arrhythmia are alsoprovided.

BACKGROUND

Ion channels are proteins that span the lipid bilayer of the cellmembrane and provide an aqueous pathway through which specific ions suchas Na⁺, K⁺, Ca²⁺and Cl⁻ can pass (Herbert, 1998). Potassium channelsrepresent the largest and most diverse sub-group of ion channels andthey play a central role in regulating the membrane potential andcontrolling cellular excitability (Armstrong & Hille, 1998). Potassiumchannels have been categorized into gene families based on their aminoacid sequence and their biophysical properties (for nomenclature seeGutman et al., 2003).

Compounds which modulate potassium channels have multiple therapeuticapplications in several disease areas including autoimmune,inflammatory, cardiovascular, neuronal, auditory, renal and metabolicmediated diseases (Shieh et al., 2000; Ford et al., 2002, Xie et al,2004, Cahalan et al, 1997). The potassium channel Kv1.3 is found in anumber of tissues including neurons, blood cells, osteoclasts,macrophages, epithelia, and T- and B-lymphocytes. Furthermore, Kv1.3inhibition has been shown to modulate T-cell function which hasimplications in many autoimmune diseases including psoriasis, rheumatoidarthritis, multiple sclerosis, obesity, diabetes and inflammatory boweldisease (Beeton et al., 2006).

Kv1.3 Channel Blockers for Autoimmune Disorders

The role of autoreactive, late-stage, memory T-cells in the pathogenesisof a variety of autoimmune diseases including psoriasis, rheumatoidarthritis, multiple sclerosis, IBD and others is well established.Activation of T_(EM) cells is followed by substantial up-regulation ofKv1.3 channel expression and, as a result, Kv1.3 becomes the predominantroute of potassium efflux from the cell. Thus, selective blockade of

Kv1.3 causes membrane depolarisation and inhibition of Ca²⁺ influx,leading to inhibition of cytokine production and cell proliferation andfunction. Kv1.3 thus represents a novel therapeutic target of greatinterest for autoimmune disease control.

T-cells and Autoimmunity

T-cells are lymphocytes which play a central role in cell mediatedimmunity. One of the major forms of T-cell is the helper T-cell (T_(H)),also known as CD4+ cells which plays an essential role in thedevelopment of autoimmune diseases. Through the production of thecytokine interleukin 2 (IL-2), CD4+ T-cells can create the second maintype of T-cell known as cytotoxic T-cells (CD8+). Naïve (inactive) CD4+and

CD8 T-cells express both proteins (CCR7 CD45RA+) and use the chemokinereceptor CCR7 as a key to gain entry into lymph nodes. Within lymphnodes, the naïve T-cells encounter antigen and through an activationprocess, change into “effector” T-cells that produce cytokines andproliferate. Once the ensuing immune response subsides, most naïveeffectors die, but a few differentiate into long-lived central memorycells (T_(CM)). T_(CM) cells, like naïve cells, use CCR7 to home to thelymph nodes to encounter their cognate antigen. Upon antigenicstimulation, T_(CM) cells change into “T_(CM) effector” cells thatproduce cytokines and proliferate. They too suffer the same fate asnaïve effectors, the majority dying after the immune response wanes,leaving a few long-lived survivors for further challenge. Repeatedantigenic challenge, as might happen in autoimmune diseases or inchronic infections, causes T_(CM) cells to differentiate intoshort-lived “effector memory T-cells” (T_(EM)) that lack expression ofboth CCR7 and CD45RA, and do not need to home to lymph nodes forantigen-induced activation. A subset of CD8 T_(EM) cells reacquireCD45RA and become CCR7-CD45RA+ T_(EMRA) cells. Upon activation, bothCD4+ and CD8+ T_(EM) cells change into T_(EM) effectors that migraterapidly to sites of inflammation and produce large amounts of theproinflammatory cytokines, interferon-γ (IFN-γ) and tumor necrosisfactor a (TNFα). In addition, CD8+ T_(EM) effectors carry large amountsof perforin and are therefore immensely destructive (Wulff et al, 2003,Beeton et al, 2005).

Functional Role of Kv1.3 in T-cells and Autoimmune Disorders

Human T-cells express two K⁺ channels, Kv1.3 and IKCa1, that provide thecounterbalance cation efflux necessary for the sustained elevation ofcytosolic Ca²⁺ levels required for gene transcription, proliferation andcytokine secretion (Panyi et al, 2004, Chandy et al, 2004). The Kv1.3and IKCa1 (also known as KCa3.1) channels regulate membrane potentialand facilitate Ca²⁺ signaling in T-lymphocytes. Kv1.3 opens in responseto membrane depolarisation and maintains the resting membrane potential(initiation phase), whereas IKCa1 opens in response to an increase incytosolic Ca²⁺ and hyperpolarises the membrane potential (Beeton et al,2001). Selective blockade of K⁺ channels leads to membranedepolarisation, which in turn inhibits Ca²⁺ influx and shuts downcytokine production and cell proliferation. Early in vitro studies,using channel blocker toxins, clearly demonstrate that Kv1.3 channelsare essential for the synthesis (gene activation) and secretion of thecytokine IL-2 after T-cell activation (Price et al, 1989) and provide arationale for the potential therapeutic use of inhibitors of thischannel in immunological disorders. The role of autoreactive T-cells inthe pathogenesis of autoimmune diseases has clearly been demonstrated inanimal models. Disease-specific, autoreactive T-cells in several otherautoimmune diseases are also reported to exhibit a memory phenotype.Autoreactive T_(EM) cells are also implicated in psoriasis, rheumatoidarthritis, multiple sclerosis, IBD, vitiligo, uveitis, pemphigus,inflammatory myopathies, Hashimito disease, and scleroderma (Beeton etal, 2005). “Late” memory T- and B-cells have been implicated in thedisease progression and tissue damage in a number of autoimmunediseases, in transplant rejection and chronic graft-versus-host disease.Modulators of the Kv1.3 channel may allow selective targeting ofdisease-inducing effector memory T-cells and memory B-cells withoutcompromising the normal immune response and as a result are likely tohave a preferred side-affect profile than agents that bring about moregeneral immunosuppression.

The observation that the Kv1.3 blocker margatoxin (MgTX) effectivelysuppressed the delayed-type hypersensitivity (DTH) response in vivo wasprovided by Koo et al, 1999. In addition MgTX was also shown to inhibitprimary antibody response in non-sensitised animals (secondary antibodyresponse was not affected by MgTX. These latter results are in agreementwith the notion that Kv1.3 channels are predominant in resting Tlymphocytes and regulate their function, while IKCa1 channels are moreimportant in pre-activated T lymphocytes. Correolide (Koo et al, 1999)and PAP-1 (Schmitz et al, 2005) are novel immunosuppressants which blockKv1.3 channels and are effective in the DTH model. Because the cellularcomponents involved in DTH response are similar to those found inautoimmune diseases and allograft rejection, the results obtained arevery promising for the development of Kv1.3 channel blockers as newimmunosuppressants.

In the early 1980's a number of compounds were reported to block Kv1.3channels at micromolar to millimolar concentrations as described byTriggle et al, in “Voltage Gated Ion Channels as Drug Targets” theseinclude classical Kv channel inhibitors such as 4-aminopyridine andtetramethylammonium, and other non specific compounds such as thecalcium activated potassium channel blockers quinine and ceteidil, thephenothiazine antipscychotics chloropromazine and trifluoroperazine, theclassical calcium channel inhibitors verapamil, diltiazem, nifedipineand nitrendipine, and the beta blocker propranolol.

Also in the 1980's natural products extracted from scorpions, snakes andother marine organisms were found to be potent inhibitors of Kv1.3channels, these were primarily short peptides (<70 residues) that arestabilised by multiple sulphide bonds. The first of these potentinhibitors was isolated from the venom of the scorpion Leiurusquinquestriatus hebraeus and was named charybdotoxin (ChTX) (Sands etal, 1989), there after screening of other scorpion venoms led to theidentification of more potent Kv1.3 blocking toxins, these includemargatoxin (MgTX) (Garcia et al, 1993), agitoxin-2 (Garcia et al, 1994),hongotoxin (Koshchak et al, 1998), pandinus imperator toxin 2 (Pi2)(Peter et al, 2001) and orthochirus scrobiculosus (OSK1) (Mouhat et al,2005) among others. With the exception of OSK1 (300 fold selective overthe nearest related channel) none of the scorpion toxins were selectivefor Kv1.3.

One of the most potent and selective Kv1.3 blockers to date, which wasextracted from sea anemone is stichodactyla helianthus toxin (Shk)(Pennington et al, 1996) this has been reported for the treatment ofautoimmune disease through the blockade of Kv1.3 (U.S. Pat. No.6,077,680). Shk and its synthetic derivative Shk-Dap²² with improvedselectivity profile display pico molar activity (Pennington et al, 1998)however, these peptides proved to have unfavourable properties forfurther development.

Recently more novel and selective small molecule Kv1.3 channel blockershave been reported for the management of autoimmune disorders. Theseinclude the iminodihydroquinolines WIN173173 and CP339818 (Nguyen etal., 1996), the benzhydryl piperidine UK-78,282 (Hanson et al. 1999),correolide (Felix et al., 1999), cyclohexyl-substituted benzamide PAC(US-06194458, WO0025774), sulfamidebenzamidoindane (US-06083986),Khellinone (Baell et al., 2004), dichloropenylpyrazolopyrimidine(WO-00140231) and psoralens (Wulff et al., 1998., Vennekamp et al.,2004, Schmitz et al., 2005).

Substituted arylsulfonamides have been reported widely to be usefulligands for intervention in a number of therapeurtic areas, these rangefrom inhibitors of 11-beta-hydroxysteroid dehydrogenase typel, for thetreatment and prevention of hyperglycemia in diseases such as type-2diabetes (WO2004065351), inhibitors of mitotic kinesins as effectiveanti cancer agents (WO2007056078), inhibitors of Factor Xa useful in thetreatment of arterial and venous thrombotic occlusive disorders,inflammation, cancer and neurodegenerative diseases (WO96/40100),inhibitors of BACE as an effective means for treating and preventingAlzheimer's and related diseases caused by the production ofbeta-amyloid (WO2005/030709). They have also been claimed as liver Xreceptor (LXR) modulators useful for the treatment or prevention ofdiseases associated with the activity of LXR's (WO2003082205) and forthe treatment or prophylaxis of viral diseases, in particular for thetreatment of Hepatitis C (WO 2007/110171).

Substituted bicyclic tertiary arylsulphonamides have been reported to beuseful as inhibitors of glycogen associated protein phospharasel (PP1)for the prevention of metabolic disorders, particularly diabetes(WO2008113760); inhibitors of alpha2C adrenergic receptors for treatingglaucoma, chronic pain, migraines, heart failure and psychotic disorders(WO2007024944); inhibitors of Kvl voltage dependent potassium channels,through interruption of the interaction of the Kv channel with the Kvbeta subunit, for treating a range of conditions from urinary tractdisorders to pain, cardiac disorders to cell proliferative and metabolicdisorders such as malignancy and diabetes (WO2008038053); and asantithrombotic agents with potential application in treating deep veinthrombosis and preventing occlusion in conditions such as stroke (U.S.Pat. No. 63000342).

It has now surprisingly been found that compounds of general formula (I)set out below act as inhibitors of potassium channels. These compoundsare particularly useful for inhibiting the potassium channel Kv1.3 andtreating diseases associated with the inhibition of the potassiumchannel Kv1.3. This invention is not limited to treating diseasesmediated by Kv1.3, the compounds also being useful to treat diseaseswhich require Kv1.5 potassium channel inhibition for example atrialfibrillation (Marban, 2002, Brendel and Peukert, 2002).

DESCRIPTION OF PRESENT INVENTION

Thus, in a first aspect, the present invention provides a compound offormula (I)

Or its salts or pharmaceutically acceptable derivatives thereof wherein;

A represents a chemical moiety with the general formula (II):

X is selected from a group consisting of CH₂, C(═O), CH(R₅), C(R₅)(R₆)or C(R₅)(R₆)CH₂;

R₁ is selected from the group consisting of optionally substitutedarylalkyl, and optionally substituted heteroarylalkyl;

R₂ is selected from the group consisting of optionally substituted arylor optionally substituted heteroaryl or NR₇R₈;

R₃ is selected from the group consisting of hydrogen, halogen, hydroxyl,alkoxy, aryloxy, optionally substituted alkyl, optionally substitutedamino, optionally substituted amino sulfonyl or nitrile;

R₄ is selected from the group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted sulfamoyl, optionallysubstituted aryl, optionally substituted arylalkyl, and optionallysubstituted heteroaryl;

R₅ and R₆ for each occurrence is optionally substituted alkyl;

R₇ and R₈ are the same or different and each represents hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted arylalkyl, optionally substituted aryl oroptionally substituted heteroaryl;

n=1 or 2,

with the proviso that

when X is C(R₅)(R₆)CH₂, n is 1

As used herein, the following definitions shall apply unless otherwiseindicated.

The term “optionally substituted” means that a group may be substitutedby one or more substituents which may be the same or different. Whenotherwise not specified, these substituents are selected from alkyl,cycloalkyl, —O—C(halogen)₃ preferably —OCF₃, biaryl, carbocyclic aryl,heteroalicyclic, heteroaryl, acyl, amidino, amido, amino, alkyoxyamino,carbamoyl, carboxy, cyano, ether, hydroxyl, imino, halo, nitro,sulphamoyl, sulfonyl, sulphinyl, sulphenyl, sulfonamido or urea.

The term “alkyl group” as used herein, is typically a linear or branchedalkyl group or moiety containing from 1 to 6 carbon atoms, preferably 2,3, 4, or 5 carbon atoms such as a C₁₋₄ alkyl group or moiety, forexample methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl and t-butyl.An alkyl group or moiety may be unsubstituted or substituted at anyposition. Typically, it is unsubstituted or carries one two or threesubstituents. Suitable substituents include cyano, halogen, hydroxyl,alkylamino, dialkylamino, amido, alkylamido, dialkylamido, alkanoyl,alkoxy, sulfonamido, nitro, aryl and heteroaryl. The alkyl moiety mayalso be an “unsaturated alkyl” moiety, which means that it contains atleast one alkene or alkyne moiety. An “alkene” moiety refers to a groupconsisting of at least two carbon atoms and at least one carbon-carbondouble bond. An “alkyne” moiety refers to a group consisting of at leasttwo carbon atoms and at least one carbon-carbon triple bond.

The term “cycloalkyl” as used herein refers to mono- or bicyclic ring orring systems consisting of 3 to 11 carbon atoms i.e. 3, 4, 5, 6, 7, 8,9, 10 or 11 carbon atoms. The ring system may be a “saturated ring”,which means that the ring does not contain any alkene or alkynemoieties. The cycloalkyl group may also be an “unsaturated ring” whichmeans that it contains at least one alkene or alkyne moiety and the ringsystem is not aromatic. The cycloalkyl group may be unsubstituted orsubstituted as defined herein. In addition to the above mentionedsubstituents one or more ring carbon atoms may also be bonded via adouble bond to a group selected from NH, S and O. The cycloalkylsubstituent may be bonded via a linker group such as a C₁₋₆ alkyl group,except where the optional substituent is alkyl. One or more hydrogens ofthe alkyl group in the linker may be replaced by a moiety selected fromthe group consisting of hydroxy, halo, cyano, amino, thiol, C₁₋₆alkoxy,C₁₋₆alkylthio, C₁₋₆alkylamino and C₁₋₆dialkylamino.

The term “aryl group” as used herein, is typically a C₆₋₁₀ aryl groupsuch as phenyl or naphthyl. A preferred aryl group is phenyl. An arylgroup may be unsubstituted or substituted at any position. Typically, itcarries 1, 2, 3 or 4 substituents. Suitable substituents include cyano,halogen, hydroxyl, nitro, trifluoromethyl, alkyl, alkylthio, alkoxy,amino, alkylamino, dialkylamino, alkanoyl, amido, N-alkylamido,NN-dialkylamino, sulfonamido, aryl and heteroaryl.

The term “carbocyclic” refers to a compound which contains one or morecovalently closed ring structures and the atoms forming the backbone ofthe ring(s) are all carbon atoms. The term thus distinguishescarbocyclic from heterocyclic rings. Carbocyclic groups include both, a“cycloalkyl group”, which means a non-aromatic carbocycle, and a“carbocyclic aryl” group, which means an aromatic carbocycle. Thecarbocyclic group may optionally be substituted as defined herein.

The term “heterocyclic” or “heterocyclo” as used herein refers to mono-or bicyclic rings or ring systems which include one or more heteroatomsselected from N, S and O. The rings or ring systems include 1 to 6carbon atoms in addition to the heteroatom(s). The term heterocyclicgroup include both a “heteroalicyclic” group, which means a non-aromaticheterocycle and a “heteroaryl” group, which means an aromaticheterocycle. The heterocyclic moiety may be unsubstituted or substitutedas defined herein and the substituents, when positioned adjacent to oneanother, may combine to form cycloalkyl or heteroalicyclic ring systemsfor example methylendioxy or difluoromethylendioxy. The heterocyclicsubstituent may be bonded via a carbon atom or a heteroatom. Theheterocyclic group may also include the oxides of nitrogen and sulfur ifnitrogen or sulfur are present in the ring.

The term “heteroaryl” as used herein refers to mono- or bicyclic ring orring systems which include one or more heteroatoms selected from N, Sand O. The rings or ring systems include 1 to 13 carbon atoms inaddition to the heteroatom(s) and contain at least one aromatic ringwith a heteroatom. The heteroaryl group may also include the oxides ofnitrogen and sulfur if nitrogen or sulfur is present. Examples ofmonocyclic heteroaryl groups include, but are not limited to, furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples ofbicyclic heterocycles include but are not limited to indolyl,benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl,benzisoxazolyl, benzisothiazolyl, indazolyl, isoquinolinyl, quinolinyl,quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl andthe like. Examples of tricyclic heterocycles include but are not limitedto thianthrenyl, xanthenyl, phenoxathiinyl, carbazolyl, carbolinyl,phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl,phenothiazinyl and phenoxazinyl. The heteroaryl group may beunsubstituted or substituted as defined herein. The substituents, whenpositioned adjacent to one another, may combine to form a cycloalkyl orheteroalicyclic ring for example methylendioxy anddifluoromethylendioxy. The heteroaryl substituent may be bonded via acarbon atom or a heteroatom.

The term “arylalkyl”, as used herein, refers to a chemical moiety offormula aryl-C₁₋₆alkyl or C₁₋₆alkyl- aryl as those terms are definedherein.

The term “heteroarylalkyl”, used as herein, refers to a chemical moietyof formula heteroaryl-C₁₋₆alkyl or C₁₋₆alkyl-heteroaryl as those termsare defined herein.

The term “acyl”, as used herein, refers to a chemical moiety of formula(CH₂)yC(═O)Rz wherein y is 1-6

The term “amidino” refers to a chemical moiety with the formula(CH₂)yC(═NH)NRzR′z wherein y is 1-6.

The term “amido” refers to both, a “C-amido” group which means achemical moiety with the formula —C(═O)NRzR′z and a “N-amido” groupwhich means a chemical moiety with the formula —NRzC(═O)R′z.

The term “amine” or “amino” refers to a chemical moiety of formula—NRzR′z. The definition of an amine is also understood to include theirN-oxides.

A “cyano” group refers to a chemical moiety of formula —CN.

The term “hydroxy” or “hydroxyl” as used herein, refers to a chemicalmoiety of formula —OH.

The term “halogen” or “halo” refers to an atom selected from the groupconsisting of fluorine, chlorine, bromine and iodine.

The term “alkanoyl”, as used herein, refers to a chemical moiety withthe formula —C(=O)Rz.

The term “sulfone” or “sulfonyl” refers to a chemical moiety with theformula —S(═O)₂Rz.

The term “sulfinyl” refers to a chemical moiety with the formula—S(═O)Rz.

The term “sulfenyl” refers to a chemical moiety with the formula —SRz.

A “sulfamoyl” group refers to a chemical moiety with the formula—NRz-S(═O)₂NRzR′z.

The term “sulfonamido” refers to both an “S-sulfonamido” group whichmeans a chemical moiety with the formula —S(═O)₂NRzR′z and an“N-sulfonamido” group which means a chemical moiety with the formula—N—S(═O)₂R′z.

The term “thiocarbonyl” refers to a chemical moiety with the formula(CH₂)yC(═S)Rz wherein y is 1-6.

The term “thio” or “thiol”, as used herein, refers to a chemical moietyof formula —SH.

The term “thioamide” refers to both a “C-thioamido” group which means achemical moiety with the formula (CH₂)yC(═S)NRzR'z and a “N-thioamido”group which means a chemical moiety with the formula (CH₂)yNRzC(═S)R′zwherein y is 1-6.

An “urea” group refers to a chemical moiety of formula —NRzC(═O)NRzR′z.

Rz and R′z are independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, cycloalkyl, C₁₋₆alkoxy, aryl-C₁₋₆alkyl, aryl andheteroaryl.

In a preferred embodiment:

X is CH₂, C(═O) or C(R₅)(R₆)CH₂.

The chemical moiety A is attached to the compound of formula (I) viachemical bond at C₁, C₂ or C₃.

Preferably R₁ is a chemical moiety of formula (III):

Wherein:

R₉, R₁₀, R₁₁, R₁₂ and R₁₃ are the same or different and each representshydrogen, halogen, hydroxyl, optionally substituted amino, optionallysubstituted acyl, nitrile, optionally substituted C₁₋₃ alkyl oroptionally substituted alkoxy;

R₁₄ and R₁₅ are the same or different and each represents hydrogen,hydroxyl, and optionally substituted C₁₋₃ alkyl. Preferably R₁₀, R₁₁ andR₁₂ are the same or different and each represents H, Cl, F, or CH₃.

R₂ is selected from compounds of formula (IV), (V) or (VI):

Wherein:

A, D, E, G, and J are the same or different and each represents C, or Nwith the proviso that in each instance at least one of A, D, E, G, or Jis N;

When R₂ is selected from compounds of formula (IV), E may also representO or S; and

When R₂ is selected from compounds of formula (V), A may also representO or S;

Preferred moities of formula (IV), (V) and (VI) are Imidazole, Pyrazole,Pyrrole, Oxazole, Oxadiazole, Thiazole, Thiadiazole, Pyridine,Pyrimidine, Pyrazine, Pyridazine, and Triazine. More preferably R₂ isselected from Imidazole, Pyrazole, or Pyridine.

R₁₆ and R₁₇ are the same or different and each represents hydrogen,halogen, hydroxyl, nitrile, optionally substituted amino, optionallysubstituted acyl, optionally substituted C₁₋₃ alkyl, optionallysubstituted arylalky, optionally substituted aryl or optionallysubstituted heteroaryl or may be taken together to form an optionallysubstituted saturated or partially saturated 5-7 membered heterocyclicor carbocyclic ring.

Preferably R₁₆ and R₁₇ are alkyl, more preferably CH₃.

Alternatively, R₂ is selected from compounds of formula (VII)

R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are the same or different and eachrepresents hydrogen, halogen, hydroxyl, optionally substituted amino,optionally substituted acyl, nitrile, optionally substituted C₁₋₃ alkyl,any of the pairs R₁₈ and R₁₉, or R₁₉ and R₂₀, or R₂₀ and R₂₁, or R₂₁ andR₂₂ or may be taken together to form an optionally substituted saturatedor partially saturated 5-7 membered heterocyclic or carbocyclic ring.

Preferred moities of formula (VII) include phenyl, fluorophenyl,chlorophenyl, cyanophenyl, aminophenyl, acetamidophenyl,tetrahydrobenzofuran, benzopyran, dihydrobenzodioxin, benzoxazinone,benzooxadiazole, benzodioxole, indoline, indole, indazole, andbenzomorpholine. Preferably (VII) is selected from phenyl, fluorophenyl,cyanophenyl, tetrahydrobenzofuran, benzopyran, dihydrobenzodioxin,benzoxazinone, benzooxadiazole, benzodioxole, indoline, andbenzomorpholine.

Preferably R₃ is H, F or CH₃. More preferably R₃ is H.

R₄ is preferably selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted acyl,optionally substituted arylalkyl, and optionally substituted heteroaryl.Preferred examples include hydrogen, methyl, ethyl, propyl, isopropyland 2-hydroxyethyl.

R₅ and R₆ are optionally substituted alkyl. More preferably, R₅ and R₆are CH₃.

More preferred compounds are those where A is represented by formula(VIII);

Wherein:

R₂ is selected from compounds of formula (III), (IV) (V) or (VI), andR₉, R₁₀, R₁₁, R₁₂ and R₁₃ are defined as above.

Most preferred compounds are those selected from compounds of formula(I) where the core structure is represented by (IX), (X), (XI);

Wherein;

A is a chemical moiety of formula (VIII), and R₃ and R₄ are as definedabove.

Particularly preferred compounds of the invention include:

1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

Pyridine-3-sulfonic acid(40chloro-benzyl)-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-amide

N-(4-Chloro-benzyl)-3-cyano-N-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide

Pyridine-3-sulfonic acid(4-chloro-benzyl)-[2-(2-hydroxy-ethyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide

1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

N-(4-Chloro-benzyl)-3-cyano-N-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide

1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(2-methyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-[2-(2-hydroxy-ethyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide

N-(4-Chloro-benzyl)-3-cyano-n-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamide

N-(4-Chloro-benzyl)-3-cyano-N-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)benzene sulfonamide

Pyridine-3-sulfonic acid(4-chloro-benzyl)-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-amide

Pyridine-3-sulfonic acid94-chloro-benzyl)-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-isopropyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-amide

1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-amide

1-Methyl-1H-pyrazole-3-sulfonic acid benzyl(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide

1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-amide

1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-amide

1-Methyl-1H-imidazole-4-sulfonic acidbenzyl-(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide.

As used herein, a pharmaceutically acceptable salt is a salt with apharmaceutically acceptable acid or base. Pharmaceutically acceptableacids include both inorganic acids such as hydrochloric, sulphuric,phosphoric, diphosphoric, hydrobromic or nitric acid and organic acidssuch as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric,benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic orp-toluenesulfonic. Pharmaceutically acceptable bases include alkalimetal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium ormagnesium) hydroxides and organic bases such as alkyl amines, arylalkylamines or heterocyclic amines.

The compounds of the invention may contain one or more chiral centres.For the avoidance of doubt, the chemical structures depicted herein areintended to embrace all stereo isomers of the compounds shown, includingracemic and non racemic mixtures and pure enantiomers and/ordiastereoisomers.

As discussed herein, the compounds of the invention are useful in thetreatment of various conditions. Thus, in a second aspect, the presentinvention provides a compound of formula (I) as defined herein for usein medicine. Preferably the compound is used to prevent or treatconditions which require inhibition of potassium channels, such asimmunological disorders, including psoriasis, rheumatoid arthritis andmultiple sclerosis.

In a further aspect the present invention provides a pharmaceuticalformulation comprising at least one compound of formula (I) or asdefined herein and optionally one or more excipients, carriers ordiluents.

The compositions of the invention may be presented in unit dose formscontaining a predetermined amount of each active ingredient per dose.Such a unit may be adapted to provide 5-100 mg/day of the compound,preferably either 5-15 mg/day, 10-30 mg/day, 25-50 mg/day 40-80 mg/dayor 60-100 mg/day. For compounds of formula I, doses in the range100-1000 mg/day are provided, preferably either 100-400 mg/day, 300-600mg/day or 500-1000 mg/day. Such doses can be provided in a single doseor as a number of discrete doses. The ultimate dose will depend on thecondition being treated, the route of administration and the age, weightand condition of the patient and will be at the doctor's discretion.

The compositions of the invention may be adapted for administration byany appropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For applications to the eye or other external tissues, for example themouth and skin, the formulations are preferably applied as a topicalointment or cream. When formulated in an ointment, the active ingredientmay be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredient may be formulated in a creamwith an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administration to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists which may be generated by means ofvarious types of metered dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

Preferred unit dosage formulations are those containing a daily dose orsub-dose, as herein above recited, or an appropriate fraction thereof,of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may also include other agentsconventional in the art having regard to the type of formulation inquestion, for example those suitable for oral administration may includeflavouring agents.

The compositions of the invention can be used to treat conditions whichrequire inhibition of potassium channels, for example in the treatmentof immunological disorders and arrythmia. Thus, in further aspects, thepresent invention provides:

(i) A method of treating or preventing a disorder which requirespotassium channel inhibition, eg immunological disorders comprisingadministering to a subject an effective amount of at least one compoundof the invention or a pharmaceutical composition of the invention and

(ii) the use of a compound of the invention in the manufacture of amedicament for use in potassium channel inhibition.

In particular, the medicament is for use in the treatment or preventionof psoriasis, rheumatoid arthritis, multiple sclerosis otherimmunological disorders and arrhythmia.

Methods

The compounds of formula (I) may be prepared by conventional routes, forexample those set out in Schemes 1-4 shown below.

Compounds of formula (I) in which R₄ is H, alkyl or optionallysubstituted alkyl, and X is C═O or CH₂ or C(R₅)(R₆)CH₂, and R₁ R₂, R₃,and n are defined as above, may be prepared as in Scheme 1 fromsulphonamides of the formula (XIII) in which X, R₂, R₃, R₄ and n aredefined as above utilizing standard methods familiar to those skilled inthe art such as, reaction with an electrophile of the formula R₁-Y whereR₁ is defined as above and Y is Cl or Br in the presence of a base, forexample cesium carbonate and a solvent such as tetrahydrofuran,acetonitrile or dichloromethane at a range of temperatures from ambientto reflux temperature. Alternatively, compounds of formula (I) in whichX, R₁ R₂, R₃, R₄ and n are defined as above may be prepared from aminesof the formula (XII) in which X, R₁, R₃, R₄ and n are defined as aboveby standard methods familiar to those skilled in the art such as,reaction with a sulfonyl or sulfamoyl chloride with the formula R₂SO₂Clin which R₂ is defined as above, in the presence of a base, for examplepyridine, triethylamine or potassium carbonate and a solvent such astetrahydrofuran, acetonitrile or dichloromethane, at a range oftemperatures from ambient to reflux temperature. It is obvious andunderstood by those skilled in the art that compounds of formula (I)where R₄ is H may be converted to compounds of formula (I) where R₄ isalkyl or optionally substituted alky by reacting with a compound withthe formula R₄-Y where R₄ is defined as alkyl or optionally substitutedalkyl and Y is Cl or Br. Typically, this reaction is carried out in thepresence of a strong base, for example sodium hydride, a solvent such astetrahydrofuran or dimethylformamide at a range of temperatures fromambient to reflux temperatures using microwave or conventional heating.

Compounds of formula (XIII) in which X, R₂, R₃, R₄ and n are defined asabove, may be prepared from compounds of formula (XIV) in which X, R₃,R₄ and n are defined as above by standard methods familiar to thoseskilled in the art, such as reaction with a sulfonyl or sulfamoylchlorides with the formula R₂SO₂Cl in which R₂ is defined as above, inthe presence of a base, for example potassium carbonate, triethylamineor pyridine, and a solvent such as dichloromethane, tetrahydrofuran andacetonitrile, at a range of temperatures from ambient to refluxtemperature.

Compounds of formula (XII) in which X, R₁, R₃, R₄ and n are defined asabove, may be prepared from compounds of formula (XIV) in which X, R₃,R₄ and n are defined as above, by standard methods familiar to thoseskilled in the art such as, alkylation with an electrophile with theformula R₁-Y where R₁ is defined as above and Y is Cl or Br in thepresence of a base, for example potassium carbonate, triethylamine orpyridine and a solvent such as dichloromethane, tetrahydrofuran andacetonitrile at a range of temperatures from ambient to refluxtemperature. Alternatively, compounds of formula (XII) in which X, R₁,R₃, R₄ and n are defined as above, may be prepared from compounds offormula (XIV) in which X, R₃, R₄ and n are defined as above, by standardmethods familiar to those skilled in the art, such as reductiveamination with an aldehyde of the formula R₁C═O where R₁ is defined asabove in the presence of a reducing agent, for example sodiumtriacetoxyborohydride, and a solvent such as dichloromethane,tetrahydrofuran and acetonitrile at ambient temperature. Alternatively,compounds of formula (XII) in which R₄ is H and X, R₁, R₃ and n aredefined as above, may be prepared from compounds of formula (XVI) inwhich X, R₃ and n are defined as above, by standard methods familiar tothose skilled in the art, such as nucleophilic substitution (SnAr) of afluorinated aryl system, bearing an electron sink such as the amide,with a primary amine with formula R₁NH₂ in which R₁ is defined as above,in the presence of a base, for example potassium carbonate at hightemperatures using microwave or conventional heating.

Compounds of formula (XVI) in which is X is CH₂, n is 2 and R₃ isdefined as above may be prepared from compounds of formula (XVII) inwhich X is CH₂, n is 1 and R₃ is defined as above using the Schmidtreaction conditions, typically the indanone (XVII) is reacted withreacted with methanesulphonic acid and sodium azide in a solvent such asdichloromethane at or below room temperature. Fluoro substitutedindanones (XVII) are known and commercially available.

Compounds of formula (XIV) in which X, R₃, R₄ and n are defined asabove, may be prepared from compounds of formula (XV) in which X, R₃, R₄and n are defined as above, by standard methods familiar to thoseskilled in the art such as such as reduction using a reducing agent, forexample Palladium/carbon (10% wt) and ammonium formate ortin(II)chloride in a suitable solvent such as dimethylformamide orethanol, at ambient of temperatures.

Compounds of the formula (XV) in which X, R₃, R₄ and n are defined asabove may be prepared by conventional routes described in Schemes 2-4below

Compounds of formula (XV) in which R₃, R₄ are defined as above may beprepared as in Scheme 2 from compounds of the formula (XVIII) in which Yis Br, Cl or any suitable leaving group and R₃ is defined as above,utilizing standard methods familiar to those skilled in the art forexample reacting with a primary amine of the formula R₄NH₂ in which R₄is defined as above in a solvent such as tetrahydrofuran at ambienttemperatures.

Compounds of formula (XVIII) in which R₃ and Y are defined as above maybe prepared from compounds of the formula (XIX) in which R₃ is definedas above by utilizing standard methods familiar to those skilled in theart, for example halogenation with a halo-succinamide of the formula(XX) where Y is Br or Cl, in the presence of a radical initiator forexample ABCN or AIBN in a solvent such as carbon tetrachloride atambient temperatures.

Compounds of formula (XIX) in which R₃ is defined as above may beprepared from compounds of formula (XXI) in which R₃ is defined as aboveby a standard method familiar to those skilled in the art, for exampleesterification with methanol in the presence of catalytic quantities ofsulphuric acid at refluxing temperatures.

Compounds of formula (XXI) in which R₃ is defined as above are knowncompounds which are commercially available or may be prepared bystandard methods familiar to those skilled in the art.

Compounds of formula (XV) in which R₃, R₅ and R₆ are defined as abovemay be prepared as in Scheme 3 from compounds of formula (XXII) in whichR₄ is a protecting group for example para-methoxy benzyl (PMB) and R₃,R₅, and R₆ are defined as above, by standard method familiar to thoseskilled in the art using a deprotecting agent for example ceriumammonium nitrate in acetonitrile and water at a range of temperaturesfrom 0° C. to ambient.

Compounds of formula (XXII) in which R₄ is a protecting group, forexample PMB or defined as above and R₃, R₅ and R₆ are defined as abovemay be prepared from compounds of formula (XXIII) in which R₃, R₄, R₅and R₆ are defined as above by standard method familiar to those skilledin the art such as intra-molecular palladium catalysed coupling, forexample using palladium (II) acetate in the presence oftetraethylammonium chloride, sodium formate and sodium actete in asuitable solvent such as dimethyl formamdide at elevated temperatures.

Compounds of formula (XXIII) in which R₃, R₄, R₅ and R₆ are defined asabove may be prepared from compounds of formula (XXIV) in which R₃ andR₄ are defined as above, by a standard method familiar to those skilledin the art, for example reacting with an electrophile of the formula(XXV) in which R₅ and R₆ are defined as above and Y is Cl or Br in thepresence of a base, such as sodium hydride in a solvent such asdimethylformamide at a range of temperatures from −78 to 0° C.

Compounds of formula (XXIV) in which R₃ and R₄ are defined as above maybe prepared from compounds of formula (XXVI) in which R₃ is defined asabove, and a primary amine of the formula R₄NH₂ in which R₄ isparamethoxy benzyl or defined as above. Typically, this reaction iscarried out using a coupling reagent such as1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) or2-(7-aza-1H-benztriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) utilising standard methods familiar to thoseskilled in the art such as reaction in solvent such as tetrahydrofuran,acetonitrile or dimethylformamide at a range of temperatures fromambient to reflux temperature.

Compounds of formula (XXVI) are known compounds which are commerciallyavailable or may be prepared by standard methods familiar to thoseskilled in the art.

Compounds of formula (XV) in which R₃ and R₄ are defined as above may beprepared as in Scheme 4 from compounds of formula (XXVII) in which R₃ isdefined as above and an alcohol of the formula R₄—OH, where R₄ isdefined as above, utilizing the Mitsunobu reaction conditions, typicallythe reaction is carried out in the presence triphenylphosphine and anazodicarboxylate such diethylazodicarboxylate (DEAD) ordiisopropylazodicarboxylate (DIAD) in a solvent such as THF at roomambient temperature. Alternatively compounds of formula (XV) in which R₃and R₄ are defined as above may also be prepared from compounds offormula (XXVIII) in which R₃ is defined as above and primary amines ofthe formula R₄—NH₂ in which R₄ is defined as above.

Compounds of formula (XXVII) and (XXVIII) are known compounds which arecommercially available or may be prepared by standard methods familiarto those skilled in the art.

EXPERIMENTAL EXAMPLES

The HPLC analysis was conducted using one or more of the followingmethods:

Solvent: [MeCN-0.05% HCO₂H: H₂O-0.1% HCO₂H], 10-95% gradient 3 min, 95%2.5 min; Column: Phenomenex Gemini 50×4.6 mm i.d., C18 reverse phase;Flow rate: 0.75 mL/min unless otherwise indicated.

Solvent: [MeCN-H₂O/0.01% HCO₂H], 5-95% gradient 5 min, 95% 3min; Column:Phenomenex Gemini 50×4.6 mm i.d. , C18 reverse phase; Flow rate: 1.5mL/min unless otherwise indicated.

Solvent: [MeCN-H₂O/0.1% HCO₂H], 5-95% gradient 3.5 min, 95% 2 min;Column: Phenomenex Gemini 50×3 mm i.d. , C18 reverse phase; Flow rate:lmL/min unless otherwise indicated.

Solvent: [MeCN-H₂O/0.1% HCO₂H], 5-95% gradient 6 min, 95% 3min; Column:Phenomenex Gemini 50×4.6 mm i.d. , C18 reverse phase; Flow rate: lmL/minunless otherwise indicated.

The preparative HPLC purification was conducted in the following manner:Solvent: [MeCN-0.05% HCO₂H : H₂O-0.1% HCO₂H], 5-95% gradient 12 min, 95%3 min; Waters X-Bridge 100×19 mm i.d. , C18 reverse phase; Flow rate: 16mL/min unless otherwise indicated.

Example 1 1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-amide(Method A)

i) 2-Methyl-4-nitro-benzoic acid methyl ester

2-Methyl-4-nitrobenzoic acid (2.00 g, 11.00 mmol) was stirred inconcentrated sulfuric acid (0.6 ml) and methanol (25 ml) at reflux for15 hrs. Reaction was cooled and the solvent evaporated. The resultingresidue was partitioned between water and dichloromethane and theorganic phase separated. The aqueous phase was extracted withdichloromethane (x3) and the combined organics washed with brine, thendried (MgSO₄) and evaporated in vacuo to yield the title compound as apale yellow solid (1.89 g, 96%). HPLC retention time 4.39 min.

The following compound was synthesised according to the method describedusing appropriate starting materials;

2-Methyl-5-nitro-benzoic acid methyl ester

ii) 2-Bromomethyl-4-nitro-benzoic acid methyl ester

N-Bromosuccinimide (2.18 g, 12.30 mmol) was added to a stirred solutionof 2-methyl-4-nitro-benzoic acid methyl ester (2 g, 10.25 mmol) and ABCN(626 mg, 2.56 mmol) in carbon tetra-chloride (80 ml) at roomtemperature. The reaction was heated at reflux for 2 hrs and thenallowed to cool to room temperature and stirred for 15 hrs. The solventwas evaporated in vacuo and the resulting residue filtered through a padof silica (eluting with dichloromethane). The solvent was evaporated invacuo to afford the title compound as a yellow solid (2.70 g, 96%). HPLCretention time 4.49 min. Mass spectrum (ES+) m/z 256 (M+H).

The following compounds were synthesised according to the methoddescribed using appropriate starting materials or commerciallyavailable;

2-Bromomethyl-5-nitro-benzoic acid methyl ester

2-Bromomethyl-3-nitro-benzoic acid methyl ester.

iii) 2-Ethyl-5-nitro-2,3-dihydro-isoindol-1-one

2-Bromomethyl-4-nitro-benzoic acid methyl ester (1.0 g, 3.64 mmol) wasstirred in ethylamine (30 ml, 2.0M solution in THF) at room temperature.The reaction was stirred for 3 hrs, after which time the solvent wasevaporated in vacuo and the crude residue triturated with diethyl ether.The resulting orange solid was filtered and dried in a vacuum oven (40°C.) to afford the title compound (634 mg, 85%). HPLC retention time 3.56min. Mass spectrum (ES+) m/z 207 (M+H).

The following compounds were synthesised according to the methoddescribed using appropriate starting materials;

2-Ethyl-6-nitro-2,3-dihydro-isoindol-1-one

2-Ethyl-4-nitro-2,3-dihydro-isoindol-1-one

iv) 5-Amino-2-ethyl-2,3-dihydro-isoindol-1-one

Palladium/Carbon (10% wt) (63 mg, 0.30 mmol) was added to a stirredsolution of 2-ethyl-5-nitro-2,3-dihydro-isoindol-1-one (634 mg, 3.06mmol) and ammonium formate (949 mg, 15.31 mmol) in anhydrous DMF (12 ml)at room temperature. The resulting suspension was heated at reflux for 1hr, then cooled and filtered through a pad of celite. The solvent wasevaporated in vacuo and the crude residue purified by flash columnchromatography (5% methanol in dichloromethane) to yield the titlecompound as a pale yellow oil (530 mg, 98%). HPLC retention time 0.95min. Mass spectrum (ES+) m/z 177 (M+H).

The following compounds were synthesised according to the methoddescribed using appropriate starting materials;

6-Amino-2 -ethyl-2,3-dihydro-isoindol-1-one

4-Amino-2 -ethyl-2,3-dihydro-isoindol-1-one

v) 5-(4-Chloro-benzylamino)-2-ethyl-2,3-dihydro-isoindol-1-one

Sodium triacetoxyborohydride (1.28 g, 6.10 mmol) was added to a stirredsolution of 5-amino-2-ethyl-2,3-dihydro-isindol-1-one (540 mg, 3.05mmol), 4-chlorobenzaldehyde (854 mg, 6.10 mmol) and acetic acid (183 μl,3.05 mmol) in anhydrous acetonitrile (12 ml) at room temperature. Thereaction was stirred overnight and quenched with the addition of water.The organic phase was separated, washed with brine, then dried (MgSO₄)and evaporated in vacuo. The resulting residue was purified by flashcolumn chromatography (0 to 20% ethyl acetate in dichloromethane) toyield the title compound as a light brown solid (148 mg, 16%). HPLCretention time 4.23 min. Mass spectrum (ES+) m/z 301 (M+H).

The following compound was synthesised according to the method describedusing appropriate starting materials;

6-(4-Chloro-benzylamino)-2-ethyl-2,3-dihydro-isoindol-1-one

4-(4-Chloro-benzylamino)-2-ethyl-2,3-dihydro-isoindol-1-one

vi) 1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol -5-yl)-amide

To a stirred solution of5-(4-Chloro-benzylamino)-2-ethyl-2,3-dihydro-isoindol-1-one (40 mg,0.133 mmol) and pyridine (23 μM, 0.29 mmol) in dry acetonitrile (1 ml)was added 1-methyl-1H-imidazole-4-sulfonyl chloride (52 mg, 0.29 mmol)and the reaction heated to 150° C. in a microwave for 0.5 hrs. Thereaction was filtered and purified by preparative HPLC (Method B) toafford the title compound as an off white solid (17 mg, 25%). HPLCretention time 4.00 min. Mass spectrum (ES+) m/z 445 (M+H).

Other compounds prepared by Method A as described for example 1 usingthe appropriate starting materials are listed in TABLE 1.

Example 2 1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide(METHOD B)

i) 7-Benzylamino-3,4-dihydro-2H-isoquinolin-1-one

Sodium triacetoxyborohydride (1.29 g, 6.16 mmol) was added to a stirredsolution of 7-amino-3,4-dihydro-2H-isoquinolin-1-one (500 mg, 3.08mmol), 4-chlorobenzaldehyde (431 mg, 3.08 mmol) and acetic acid (183 μl,3.08 mmol) in anhydrous dichloromethane (25 ml) at room temperature. Thereaction was stirred overnight and quenched with the addition of water.The organic phase was separated, washed with brine, then dried (MgSO₄)and evaporated in vacuo. The resulting residue was purified by flashcolumn chromatography (50% ethyl acetate in dichloromethane) to yieldthe title compound as a pale yellow solid (287 mg, 16%). HPLC retentiontime 4.09 min. Mass spectrum (ES+) m/z 287 (M+H).

ii) 1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

To a stirred solution of 7-benzylamino-3,4-dihydro-2H-isoquinolin-1-one(100 mg, 0.34 mmol) and pyridine (63 μl, 0.77 mmol) in anhydrousdichloromethane (2 ml) was added 1-methyl-1H-pyrazole-3-sulfonylchloride (138 mg, 0.77 mmol) and the reaction heated at reflux for 15hrs. The reaction was cooled and the solvent evaporated in vacuo. Thecrude residue was purified by flash column chromatography (50% ethylacetate in dichloromethane) to afford the title compound as a colourlesssolid (63 mg, 41%). HPLC retention time 4.16 min. Mass spectrum (ES+)m/z 431 (M+H).

The following compound was synthesised according to the method describedusing appropriate starting materials;

N-(4-Chloro-benzyl)-3-cyano-N-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide

Pyridine-3-sulfonic acid(4-chloro-benzyl)-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

iii) 1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

To a suspension of 1-methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide (20mg, 0.046 mmol) and sodium hydride (3 mg, 0.055 mmol) in anhydrous THF(1 ml) was added iodoethane (8 μl, 0.055 mmol) and the reaction heatedto 110° C. in a microwave for 0.5 h. The solvent was evaporated in vacuoand the resulting residue purified by preparative HPLC (Method

B) to yield the title compound as a colourless solid (5 mg, 24%). HPLCretention time 4.34 min. Mass spectrum (ES+) m/z 459 (M+H).

Other compounds prepared by Method B as described for example 2 usingthe appropriate starting materials are listed in TABLE 1

Example 3N-(4-Chloro-benzyl)-3-cyano-N-[2-(2-hydroxy-ethyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-benzenesulfonamide(METHOD B)

N-(4-Chloro-benzyl)-3-cyano-N- (1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide (20 mg, 0.042 mmol)was stirred in dry DMF(5 ml) under nitrogen at 0° C. Sodium Hydride (8.8mg, 0.022 mmol) was added and the mixture stirred for 5 minutes.2-(2-bromoethoxytetrahydropyran) (33 μl, 0.022 mmol) was added and thereaction stirred for 30 minutes at 0° C. The DMF was removed in vacuoand the residue purified by prep HPLC. The residue was dissolved inMethanol (5 ml). To this solution was added 2M HCl (0.5 ml)and themixture stirred at room temperature for 10 minutes until no startingmaterial was observed on TLC (ethyl acetate). Solvents were removed andthe residue purified by prep TLC (ethyl acetate) to giveN-(4-Chloro-benzyl)-3-cyano-N-[2-(2-hydroxy-ethyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-benzenesulfonamideas a colourless oil. Yield=11.7 mg.

LCMS: ES+; 4.28 min; 496;

Other compounds prepared by Method B as described for example 2a usingthe appropriate starting materials are listed in TABLE 1.

Example 4 1-Methyl-1H-pyrazole-3-sulfonic acid benzyl(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (METHOD C)

i) 6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one

To a solution of 5-fluoro-1-indanone (1.5 g, 10 mmol) andmethanesulfonic acid (6 ml, 90 mmol) in anhydrous dichloromethane (6 ml)was added sodium azide (1.30 g, 20 mmol) whilst maintaining thetemperature of the reaction between 21 and 26° C. The reaction wasstirred for 15 hrs and then cooled in ice and basified using 5N sodiumhydroxide solution. The organic phase was separated and the aqueousphase extracted with dichloromethane (2×10 ml). The combined organicswere washed with water and brine, then dried (MgSO₄) and evaporated invacuo. The resulting residue was purified by flash column chromatography(50% ethyl acetate in dichloromethane) to afford the title compound as alight brown solid (1.0 g, 61%). HPLC retention time 3.18 min. Massspectrum (ES+) m/z 166 (M+H).

ii) 6-Benzylamino-3,4-dihydro-2H-isoquinolin-1-one

A solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (300 mg, 1.81mmol) and potassium carbonate (550 mg, 3.98 mmol) in benzylamine (1.5ml) was stirred at 180° C. in a microwave for 2 hrs. The solvent wasevaporated and the resulting residue partitioned between ethyl acetate(10 ml) and water (10 ml). The organic phase was separated, washed withbrine (10 ml), then dried (MgSO₄) and evaporated in vacuo. The cruderesidue was purified by preparative HPLC (Method A) to yield the titlecompound as a colourless solid (80 mg, 18%). HPLC retention time 3.81min. Mass spectrum (ES+) m/z 253 (M+H).

iii) 1-Methyl-1H-pyrazole-3-sulfonic acidbenzyl-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide

To a stirred solution of 6-benzylamino-3,4-dihydro-2H-isoquinolin-1-one(45 mg, 0.18 mmol) and pyridine (31 μl, 0.39 mmol) in anhydrousacetonitrile (1 ml) was added 1-methyl-1H-pyrazole-3-sulfonyl chloride(70 mg, 0.39 mmol) and the reaction heated to 150° C. in a microwave for0.5 hrs. The solvent was evaporated in vacuo and the crude residuepurified by preparative tic (5% methanol in dichloromethane) to affordthe title compound as a yellow solid (10 mg, 14%). HPLC retention time3.83 min. Mass spectrum (ES+) m/z 397 (M+H).

vi) 1-Methyl-1H-pyrazole-3-sulfonic acid benzyl(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide

To a suspension of 1-methyl-1H-pyrazole-3-sulfonic acidbenzyl-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (9 mg, 0.022mmol) and sodium hydride (2 mg of a 60% dispersion in mineral oil, 0.045mmol) in anhydrous THF (0.5 ml) was added iodoethane (2 μl, 0.045 mmol)and the reaction heated to 110° C. in a microwave for 0.5 hrs. Thesolvent was evaporated in vacuo and the resulting residue purified bypreparative HPLC (Method B) to yield the title compound as a colourlesssolid (4 mg, 24%). HPLC retention time 4.14 min. Mass spectrum (ES+) m/z425 (M+H).

Other compounds prepared by Method C as described for example 4 usingthe appropriate starting materials are listed in TABLE 1

Example 5 1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide(METHOD D)

i) 2-Bromo-N-ethyl-5-nitro-benzamide

To a stirred solution of HATU (501 mg, 1.32 mmol),2-bromo-5-nitrobenzoic acid (325 mg, 1.32 mmol) and diisopropylethylamine (642 μl, 3.90 mmol) in anhydrous acetonitrile (20 ml) at roomtemperature was added ethylamine (725 μl of a 2.0M solution in THF, 1.45mmol) and the reaction stirred for 15 hrs. The solvent was evaporated invacuo and the crude residue purified by flash column chromatography (20%ethyl acetate in petroleum ether) to afford the title compound as a paleyellow solid (155 mg, 43%). HPLC retention time 3.72 min. Mass spectrum(ES+) m/z 273 (M+H).

The following compound was synthesised according to the method describedusing appropriate starting materials;

2-Bromo-N-(4-methoxy-benzyl)-5-nitro-benzamide

ii) 2-Bromo-N-ethyl-N-(2-methyl-allyl)-5-nitro-benzamide

2-Bromo-N-ethyl-5-nitro-benzamide (150 mg, 0.55 mmol) in anhydrous DMF(2 ml) was added dropwise to a stirred suspension of sodium hydride (44mg of 60% dispersion in mineral oil, 1.10 mmol) in anhydrous DMF (5 ml)at -78° C. The reaction was stirred for 0.25 hrs and then allowed towarm to 0° C. 3-Bromo-2-methylpropene (111 μl, 1.10 mmol) was then addedand the reaction stirred for a further 1 hr at 0° C., after this timethe solvent was evaporated in vacuo and the resulting residuepartitioned between water and ethyl acetate. The organic phase wasseparated, washed with brine, then dried (MgSO₄) and evaporated in vacuoto afford the title compound as a colourless solid (150 mg, 84%). HPLCretention time 4.46 min. Mass spectrum

(ES+) m/z 327 (M+H).

The following compound was synthesised according to the method describedusing appropriate starting materials;

2 -Bromo-N-(4-methoxy-benzyl)-N-(2-methyl-allyl)-5-nitro-benzamide

iii) 2-Ethyl-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

To a stirred de-gassed solution of2-bromo-N-ethyl-N-(2-methyl-allyl)-5-nitro-benzamide (150 mg, 0.46mmol), tetra-ethylammonium chloride (84 mg, 0.46 mmol), sodium formate(34 mg, 0.50 mmol) and sodium acetate (82 mg, 1.01 mmol) in anhydrousDMF (10 ml) was added palladium(II) acetate (10 mg, 0.046 mmol) and thereaction stirred at 70° C. for 15 hrs. The reaction was cooled to roomtemperature and filtered through a pad of celite. The solvent wasevaporated in vacuo and the resulting residue purified by flash columnchromatography (20% ethyl acetate in dichloromethane) to afford thetitle compound as a yellow solid (110 mg, 96%). HPLC retention time 4.21min. Mass spectrum (ES+) m/z 249 (M+H).

The following compound was synthesised according to the method describedusing appropriate starting materials;

2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

iv) 7-Amino-2-ethyl-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-onePalladium/Carbon (10% wt) (12 mg, 0.04 mmol) was added to a stirredsolution of2-ethyl-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (110 mg,0.44 mmol) and ammonium formate (137 mg, 2.21 mmol) in anhydrous DMF (6ml) at room temperature. The resulting suspension was heated at refluxfor lhr, then cooled and filtered through a pad of celite. The solventwas evaporated in vacuo and the crude residue purified by flash columnchromatography (60% ethyl acetate in dichloromethane) to afford thetitle compound as a pale yellow solid (40 mg, 98%). HPLC retention time2.99 min. Mass spectrum (ES+) m/z 219 (M+H).

v)7-(4-Chloro-benzylamino)-2-ethyl-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one

Sodium triacetoxyborohydride (77 mg, 0.36 mmol) was added to a stirredsolution of7-amino-2-ethyl-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (40 mg,0.18 mmol), 4-chlorobenzaldehyde (31 mg, 0.22 mmol) and acetic acid (11μl, 0.18 mmol) in anhydrous dichloromethane (6 ml) at room temperature.The reaction was stirred overnight and quenched with the addition ofwater. The organic phase was separated, washed with brine, then dried(MgSO₄) and evaporated in vacuo. The resulting residue was purified bypreparative tic (20% ethyl acetate in petroleum ether) to afford thetitle compound as a colourless solid (20 mg, 32%). HPLC retention time4.78 min. Mass spectrum (ES+) m/z 343 (M+H).

vi) 1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

To a stirred solution of7-(4-chloro-benzylamino)-2-ethyl-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one(17 mg, 0.05 mmol) and pyridine (9 μl, 0.11 mmol) in anhydrousacetonitrile (1 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride(20 mg, 0.11 mmol) and the reaction heated to 150° C. in a microwave for0.5 hrs. The solvent was evaporated in vacuo and the crude residuepurified by preparative tic (5% methanol in dichloromethane) to affordthe title compound as a colourless solid (5 mg, 21%). HPLC retentiontime 4.42 min. Mass spectrum (ES+) m/z 487 (M+H).

Example 6 1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide(METHOD E)

i)2-(4-methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-onethis compound was prepared according to step iii in example 4 (method D)

ii) 4,4-Dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

A solution of2-(4-methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one(1.2 g, 3.52 mmol) and cerium ammonium nitrate (5.78 g, 10.56 mmol) inacetonitrile (30 ml) and water (15 ml) was stirred at 0° C. for 1 hrs,after this time the reaction was warmed to room temperature and stirredfor a further 15 h. The solvent was evaporated in vacuo anddichloromethane added. The organic phase was separated, washed withsaturated aqueous ammonium chloride solution and brine, then dried andevaporated in vacuo. The crude residue was purified by flash columnchromatography (15% ethyl acetate in dichloromethane) to afford thetitle compound (300 mg, 39%). HPLC retention time 3.71 min. Massspectrum (ES+) m/z 221 (M+H).

iv) 7-Amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one

Palladium/Carbon (10% wt) (25 mg, 0.13 mmol) was added to a stirredsolution of 4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (250mg, 1.13 mmol) and ammonium formate (350 mg, 5.65 mmol) in anhydrous DMF(10 ml) at room temperature. The resulting suspension was then heated atreflux for 1 hrs, then cooled and filtered through a pad of celite. Thesolvent was evaporated and the crude residue purified by flash columnchromatography (5% methanol in dichloromethane) to afford the titlecompound as a pale yellow solid (210 mg, 98%). HPLC retention time 1.00min. Mass spectrum (ES+) m/z 191 (M+H).

v)7-(4-Chloro-benzylamino)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one

Sodium triacetoxyborohydride (800 mg, 3.79 mmol) was added to a stirredsolution of 7-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (220mg, 1.15 mmol), 4-chlorobenzaldehyde (324 mg, 2.31 mmol) and acetic acid(69 μl, 1.15 mmol) in anhydrous dichloromethane (10 ml) at roomtemperature. The reaction was stirred overnight and quenched with theaddition of water. The organic phase was separated, washed with brine,then dried (MgSO₄) and evaporated in vacuo. The resulting residue waspurified by flash column chromatography (20% ethyl acetate indichloromethane) to afford the title compound as a light brown solid(140 mg, 39%). HPLC retention time 4.40 min. Mass spectrum (ES+) m/z 315(M+H).

vi) 1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide

To a stirred solution of7-(4-chloro-benzylamino)-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one(20 mg, 0.06 mmol) and pyridine (12 μl, 0.14 mmol) in anhydrousacetonitrile (1 ml) was added 1-methyl-1H-imidazole-4-sulfonyl chloride(25 mg, 0.14 mmol) and the reaction heated to 150° C. in a microwave for0.5 hrs. The solvent was evaporated in vacuo and the crude residuepurified by preparative HPLC (Method A) to afford the title compound asa colourless solid (15 mg, 21%). HPLC retention time 4.07 min. Massspectrum (ES+) m/z 459 (M+H).

Other compounds prepared by Method E as described for example 6 usingthe appropriate starting materials are listed in TABLE 1

Example 7 1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-isopropyl-1,3-dioxo-2,3-dihydro-1-H-isoindol-5-yl)-amide (METHOD F)

i) 2-Isopropyl-5-nitro-isoindole-1,3-dione

To a stirred solution of 4-nitrophthalimide (2.0 g, 10.41 mmol),triphenylphosphine (11.45 mmol, 2.99 g) and iso-propanol (11.45 mmol,0.73 ml) in anhydrous THF (40 ml) was added diisopropylazodicarboxylate(2.37 g, 11.45 mmol) and the reaction stirred for 16 hrs at roomtemperature. Water and ethyl acetate were added and the organic phaseseparated, washed with brine, then dried (MgSO₄) and evaporated invacuo. The crude residue was purified by flash column chromatography(30% ethyl acetate in petroleum ether) to afford the title compound as apale yellow solid (1.27 g, 52%). HPLC retention time 4.60 min. Massspectrum (ES+) m/z 235 (M+H).

ii) 5-Amino-2-isopropyl-isoindole-1,3-dione

A solution of sodium borohydride (193 mg, 5.12 mmol) in ethanol (4 ml)was added dropwise to a stirred solution of2-isopropyl-5-nitro-isoindole-1,3-dione (1.20 g, 5.12 mmol) and tin (II)dichloride dihydrate (3.47 g, 15.36 mmol) in ethanol (40 ml) at 60° C.The resulting solution was stirred for 2 hrs, after which time thereaction was cooled to 0° C. and basified using 2M sodium hydroxide. Theaqueous phase was extracted with dichloromethane (3×20 ml) and thecombined organics washed with brine, then dried (MgSO₄) and evaporatedin vacuo. The crude residue was purified by preparative HPLC (Method D)to afford the title compound as a yellow solid (512 mg, 49%). HPLCretention time 7.2 min. Mass spectrum (ES+) m/z 205 (M+H).

iii) 5-(4-Chloro-benzylamino)-2-isopropyl-isoindole-1,3-dione

Sodium triacetoxyborohydride (1.03 g, 4.90 mmol) was added to a stirredsolution of 5-amino-2-isopropyl-isoindole-1,3-dione (0.50 g, 2.69 mmol),4-chlorobenzaldehyde (0.37 g, 2.69 mmol), and acetic acid (160 μl, 2.69mmol) in anhydrous dichloromethane (10 ml) at room temperature. Thereaction was stirred overnight and quenched with the addition of water.The organic phase was separated, washed with brine, then dried (MgSO₄)and evaporated in vacuo. The resulting residue was purified by flashcolumn chromatography (5% methanol in dichloromethane) to afford thetitle compound as a light brown solid (160 mg, 20%). HPLC retention time4.86 min. Mass spectrum (ES+) m/z 329 (M+H).

iv) 1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-isopropyl-1,3-dioxo-2,3-dihydro-1-H-isoindol-5-yl)-amide

To a stirred solution of5-(4-chloro-benzylamino)-2-isopropyl-isoindole-1,3-dione (50 mg, 0.15mmol) and pyridine (36 μl, 0.45 mmol) in anhydrous dichloromethane (2ml) was added 1-methyl-1H-imidazole-4-sulphonyl chloride (60 mg, 0.27mmol)and the reaction heated at reflux for 15 hrs. The reaction wascooled and the solvent evaporated in vacuo. The crude residue waspurified by preparative HPLC (Method D) to afford the title compound asa colourless solid (5 mg, 7%). HPLC retention time 8.14 min. Massspectrum (ES+) m/z 473 (M+H).

TABLE 1 Summary of synthesis methods, characterisation data andbiological activity LCMS (ES+) hK_(v)1.3 hK_(v)1.5 Example Ret.n m/z %inh. % inh. Number Compound Name Method time (M + H) 1 uM 300 nM 11-Methyl-1H-pyrazole- C 4.34 459 99.6 82.4 3-sulfonic acid (4-chloro-benzyl)-(2-ethyl-1-oxo- 1,2,3,4-tetrahydro- isoquinolin-7-yl)-amide 2Pyridine-3-sulfonic acid B 4.28 442 97.2 65.0 (40chloro-benzyl)-(2-ethyl-3-oxo-2,3-dihydro- 1H-isoindol-5-yl)-amide 3N-(4-Chloro-benzyl)-3- C 4.28 497 97.2 87.8 cyano-N-(1-oxo-1,2,3,4-tetrahydro-isoquinolin- 7-yl)-benzenesulfonamide 4 1-Methyl-1H-pyrazole-B 4.27 445 96.6 63.8 3-sulfonic acid (4-chloro- benzyl)-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol- 5-yl)-amide 5 Pyridine-3-sulfonic acid C 4 47396.4 76.0 (4-chloro-benzyl)-[2-(2- hydroxy-ethyl)-1-oxo-1,2,3,4-tetrahydro- isoquinolin-7-yl]-amide 6 1-Methyl-1H-imidazole- E4.42 487 96.1 70.1 4-sulfonic acid (4-chloro- benzyl)-(2-ethyl-4,4-dimethyl-1-oxo-1,2,3,4- tetrahydro-isoquinolin- 7-yl)-amide 71-Methyl-1H-pyrazole- C 4.08 432 95.5 42.6 3-sulfonic acid (4-chloro-benzyl)-(1-oxo-1,2,3,4- tetrahydro-isoquinolin- 7-yl)-amide 8N-(4-Chloro-benzyl)-3- C 2.9 452 94.6 91.2 cyano-N-(1-oxo-1,2,3,4-tetrahydro-isoquinolin- 7-yl)-benzenesulfonamide 9 1-Methyl-1H-pyrazole-C 4.28 445 94.5 76.4 3-sulfonic acid (4-chloro- benzyl)-(2-methyl-1-oxo-1,2,3,4-tetrahydro- isoquinolin-7-yl)-amide 10 1-Methyl-1H-pyrazole- C3.98 476 94.2 47.1 3-sulfonic acid (4-chloro- benzyl)-[2-(2-hydroxy-ethyl)-1-oxo-1,2,3,4- tetrahydro-isoquinolin- 7-yl]-amide 11N-(4-Chloro-benzyl)-3- B 4.53 466 93.8 86.9 cyano-n-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol- 5-yl)-benzene sulfonamide 12N-(4-Chloro-benzyl)-3- B 4.49 466 93.0 63.2 cyano-N-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol- 5-yl) benzene sulfonamide 13Pyridine-3-sulfonic acid C 2.59 428 90.5 36.0 (4-chloro-benzyl)-(1-oxo-1,2,3,4-tetrahydro- isoquinolin-7-yl)-amide 14 1-Methyl-1H-imidazole- B4.04 445 89.7 27.1 4-sulfonic acid (4-chloro- benzyl)-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol- 5-yl)-amide 15 Pyridine-3-sulfonic acid F 4.29456 88.9 70.0 94-chloro-benzyl)-(4,4- dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin- 7-yl)-amide 16 1-Methyl-1H-pyrazole- F 4.27 45988.3 64.2 3-sulfonic acid (4-chloro- benzyl)-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro- isoquinolin-7-yl)-amide 171-Methyl-1H-imidazole- G 8.14 473 79.7 58.0 4-sulfonic acid (4-chloro-benzyl)-(2-isopropyl-1,3- dioxo-2,3-dihydro-1-H- isoindol-5-yl)-amide 181-Methyl-1H-pyrazole- B 4.18 445 75.2 77.3 3-sulfonic acid (4-chloro-benzyl)-(2-ethyl-1-oxo- 2,3-dihydro-1H-isoindol- 5-yl)-amide 191-Methyl-1H-pyrazole- D 4.14 425 74.3 25.4 3-sulfonic acid benzyl(2-ethyl-1-oxo-1,2,3,4- tetrahydro-isoquinolin- 6-yl)-amide 201-Methyl-1H-imidazole- F 4.07 459 72.6 34.06 4-sulfonic acid (4-chloro-benzyl)-(4,4-dimethyl-1- oxo-1,2,3,4-tetrahydro- isoquinolin-7-yl)-amide21 1-Methyl-1H-imidazole- B 4.02 446 69.8 23.8 4-sulfonic acid(4-chloro- benzyl)-(2-ethyl-1-oxo- 2,3-dihydro-1H-isoindol- 4-yl)-amide22 1-Methyl-1H-imidazole- B 4 445 67.9 30.6 4-sulfonic acid (4-chloro-benzyl)-(2-ethyl-1-oxo- 2,3-dihydro-1H-isoindol- 5-yl)-amide 231-Methyl-1H-imidazole- D 3.91 425 58.0 26.5 4-sulfonic acid benzyl-(2-ethyl-1-oxo-1,2,3,4- tetrahydro-isoquinolin- 6-yl)-amide

REFERENCES

Herbert, “General principles of the structure of ion channels”, Am. J.Med, 104, 87-98, 1998.

Armstrong & Hille, “Voltage-gated ion channels and electricalexcitability”, Neuron, 20, 371-380, 1998.

Gutman GA et al., “International Union of Pharmacology. XLI. Compendiumof voltage-gated ion channels: potassium channels”. Pharmacol Rev. Dec;55(4):583-6, 2003.

Shieh et al., “Potassium Channels: Molecular Defects, Diseases, andTherapeutic Opportunities”, Pharmacol Rev, 52(4), 557-594, 2000.

Ford et al., “Potassium Channels: Gene Family, Therapeutic Relevance,High-Throughput Screening Technologies and Drug Discovery”, Prog DrugRes, 58, 133-168, 2002.

Xie M et al., “Ion Channel Drug Discovery Expands into New DiseaseAreas”, Current Drug Discovery, 31-33, 2004.

Cahalan M D & Chandy K G, “Ion Channels in the Immune System as Targetsfor Immunosuppression”, Current Opinion in Biotechnology, 8, 749-756,1997.

Beeton et al., “Kv1.3 channels are a therapeutic target for Tcell-mediated autoimmune diseases”, Proceeds of the National Academy ofSciences, 46, 103, 17414-17419, 2006

Wulff H, Beeton C, Chandy KG: Potassium channels as therapeutic targetsfor autoimmune disorders. (2003) Curr. Opin. Drug Dis. 6(5):640-647

Beeton C, Pennington MW, Wulff H, Singh S, Nugent D, Crossley G, KhaytinI, Calabresi P A, Chen C Y, Gutman G A, Chandy K G. Targeting effectormemory T cells with a selective peptide inhibitor of Kv1.3 channels fortherapy of autoimmune diseases. (2005) Mol Pharmacol. 67(4):1369-81.

Panyi G, Varga Z, Gaspar R. Abstract Ion channels and lymphocyteactivation. (2004) Immunology Lett. 92:55-66.

Chandy K G, Wulff H, Beeton C, Pennington M, Gutman G, Cahalan M: K+channels as targets for specific immunomodulation. TIPS. (2004)25(5):280-289

Beeton C, Barbaria J, Giraud P, Devaux J, Benoliel A, Gola M, Sabatier JM, Bernard D, Crest M, Beraud E: Selective blocking of voltage-gated K+channel improves experimental autoimmune encephalomyelitis and inhibitsT cell activation. (2001) J. Immunol. 166:936-944

Price M J, Lee S C, Deutsch C: Charybdotoxin inhibits proliferation andinterleukin-2 production of human peripheral blood lymphocytes. (1989)Proc. Natl. Acad. Sci. 86:10171-10175

Koo G C, Blake J T, Shah K, Staruch M J, Dumont F, Wunderler D L,Sanchez M, McManus O B, Sirontina-Meisher A, Fischer P, Boltz R C, GoetzM A, Baker R, Bao J, Kayser F, Rupprecht K M, Parsons W H, Tong X, Ita IE, Pivnichny J, Vincent S, Cunningham P, Hora D, Feeney W, KaczorowskiG, Springer M S: Correolide and derivatives are novel immunosuppressantsblocking the lymphocyte Kv1.3 potassium channels. (1999) Cell. Immunol.,197:99-107

Schmitz A, Sankaranarayanan A, Azam P, Schmidt-Lassen K, Homerick D,Hansel W, Wulff H: Design of PAP-1, a selective small molecule Kv1.3blocker, for the suppression of effector memory cells in autoimmunediseases. (2005) Mol. Pharmacol., 68:1254-1270

Triggle D. J, Gopalakkrishnan M, Rampe D, Zheng W: Voltage gated Ionchannels as Drug Targets, Wiley, 2005)

Sands et al,: Charabydotoxin blocks voltage-gated K⁺ channels in humanand murine T lymphocytes. J. Gen- Physiol. 1989, 93, 10061-1074.

Garcia et al, Purification, characterisation and biosynthesis ofmargatoxin, a component of Centruroides maragritatus venom thatselectively inhibits voltage-gated potassium channels, J. Biol. Chem.1993, 268, 18866-1887

Garcia et al,: Purification and characterisation of three inhibitors ofvoltage dependent K⁺ channels from Leiurus quinquesttriatus var.hebraeus. Biochemistry, 1994, 33, 6834-6839

Koshchak et al., Subunit composition of brain voltage-gated potassiumchannels determined by hongotoxin-1, a novel peptide derived fromCentruroides limbatus venom. J. Biol. Chem. 1998, 273, 2639-2644.

Peter et al, Effect of toxins Pi2 and Pi3 on human T Lymphocyte kv1.3channels: the role of Glu7 and Lys24. J. Membr. Biol. 2001, 179, 13-25

Mouhat et al, K⁺ channel types targeted by synthetic OSK1, a toxin fromOrthochirus scrobiculosus scorpion venom Biochem. J. 2005, 385, 95-104

Pennington et al, Identification of there separate binding sites on Shktoxin, a potent inhibitor of voltage dependent potassium channels inhuman T-lymphocytes and rat brain. Biochem. Biophys. Res. Commun. 1996,219, 696-701

Pennington et al, ShK-Dap²², a potent Kv1.3-specific immunosuppressivepolypeptide. J. Biol. Chem. 1998, 273, 32697-35707

Nguyen A et al., “Novel Nonpeptide Agents Potently Block the C-TypeInactivated Conformation of Kv1.3 and Suppress T Cell Activation”, Mol.Pharmacol., 50, 1672-1679, 1996.

Hanson D C et al., “UK-78,282, a Novel Piperidine Compound That PotentlyBlocks the Kv1.3 Voltage-Gated Potassium Channel and Inhibits Human TCell Activation”, Br. J. Pharmacol., 126, 1707-1716, 1999.

Felix J P et al., “Identification and Biochemical Characterization of aNovel Norterpene Inhibitor of the Human Lymphocyte Voltage-GatedPotassium Channel, Kv1.3”, Biochemistry, 38 (16), 4922-4930, 1999.

Baell J B et al., “Khellinone Derivatives as Blockers of heVoltage-Gated Potassium Channel Kv1.3: Synthesis and ImmunosuppressiveActivity” J. Med. Chem., 47, 2326-2336, 2004.

Wulff H et al., “Alkoxypsoralens, Novel Nonpeptide Blockers ofShaker-Type K⁺ Channels: Synthesis and Photoreactivity”, J. Med. Chem.,41, 4542-4549, 1998.

Vennekamp J, Wulff H, Beeton C, Calabresi P A, Grissmer S, Hansel W, andChandy K G. Kv1.3-blocking 5-phenylalkoxypsoralens: a new class ofimmunomodulators. (2004) Mol. Pharmacol.65, 1364-74.

Marban “Cardiac channelopalthies”, Nature, 415, 213-218, 213-218, 2002

Brendel and Peukert ‘Blockers of the Kv1.5 Channel for the Treatment ofAtrial Arrhythmias’, Expert Opinion in Therapeutic Patents, 12 (11),1589-1598 (2002).

1. A compound of formula (I):

Or its salts or pharmaceutically acceptable derivatives thereof wherein;A represents a chemical moiety with the general formula (II):

X is selected from a group consisting of CH₂, C(═O), CH(R₅), C(R₅)(R₆)or C(R₅)(R₆)CH₂; R₁ is selected from the group consisting of optionallysubstituted arylalkyl, and optionally substituted heteroarylalkyl; R₂ isselected from the group consisting of optionally substituted aryl oroptionally substituted heteroaryl or NR₇R₈; R₃ is selected from thegroup consisting of hydrogen, halogen, hydroxyl, alkoxy, aryloxy,optionally substituted alkyl, optionally substituted amino, optionallysubstituted amino sulfonyl or nitrile; R₄ is selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted acyl, optionally substituted sulfonyl, optionallysubstituted sulfamoyl, optionally substituted aryl, optionallysubstituted arylalkyl, and optionally substituted heteroaryl; R₅ and R₆for each occurrence is optionally substituted alkyl; R₇ and R₈ are thesame or different and each represents hydrogen, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedarylalkyl, optionally substituted aryl or optionally substitutedheteroaryl; and n=1 or
 2. 2. A compound according to claim 1 wherein:the chemical moiety A is attached to the compound of formula (I) viachemical bond at C₁, C₂ or C₃; X is CH₂, C(═O) or CR₂R₃CH₂; n=1 or 2,preferably 1 or 2 when X is CH₂ and 1 when X is C(═O).
 3. A compoundaccording to claim 2 wherein R₁ has the formula (III):

Wherein: R₉, R₁₀, R₁₁, R₁₂ and R₁₃ are the same or different and eachrepresents hydrogen, halogen, hydroxyl, optionally substituted amino,optionally substituted acyl, nitrile, optionally substituted C₁₋₃ alkylor optionally substituted alkoxy; R₁₄ and R₁₅ are the same or differentand each represents hydrogen, hydroxyl, and optionally substituted C₁₋₃alkyl. Preferably R₁₀, R₁₁ and R₁₂ are the same or different and eachrepresents H, Cl, F, or CH₃.
 4. A compound according to claim 2 wherein;R₂ is selected from compounds of formula (IV), (V) or (VI):

Wherein: A, D, E, G, and J are the same or different and each representsC, or N with the proviso that in each instance at least one of A, D, E,G, or J is N; When R₂ is selected from compounds of formula (IV), E mayalso represent O or S; and When R₂ is selected from compounds of formula(V), A may also represent O or S; preferred moieties of formula (IV),(V) and (VI) are Imidazole, Pyrazole, Pyrrole, Oxazole, Oxadiazole,Thiazole, Thiadiazole, Pyridine, Pyrimidine, Pyrazine, Pyridazine, andTriazine; more preferably R₂ is selected from Imidazole, Pyrazole, orPyridine; R₁₆ and R₁₇ are the same or different and each representshydrogen, halogen, hydroxyl, nitrile, optionally substituted amino,optionally substituted acyl, optionally substituted C₁₋₃ alkyl,optionally substituted arylalky, optionally substituted aryl oroptionally substituted heteroaryl or may be taken together to form anoptionally substituted saturated or partially saturated 5-7 memberedheterocyclic or carbocyclic ring; preferably R₁₆ and R₁₇ are alkyl, morepreferably CH₃.
 5. A compound according to claim 2 wherein: R₂ isselected from groups of formula (VII)

R₁₈, R₁₉, R₂₀, R₂₁, and R₂₂ are the same or different and eachrepresents hydrogen, halogen, hydroxyl, optionally substituted amino,optionally substituted acyl, nitrile, optionally substituted C₁₋₃ alkyl,any of the pairs R₁₈ and R₁₉, or R₁₉ and R₂₀, or R₂₀ and R₂₁, or R₂₁ andR₂₂ or may be taken together to form an optionally substituted saturatedor partially saturated 5-7 membered heterocyclic or carbocyclic ring;Preferred formula VI moieties are phenyl, fluorophenyl, chlorophenyl,cyanophenyl, aminophenyl, acetamidophenyl, tetrahydrobenzofuran,benzopyran, dihydrobenzodioxin, benzoxazinone, benzooxadiazole,benzodioxole, indoline, indole, indazole, and benzomorpholine;Preferably formula (VII) moieties are selected from phenyl,fluorophenyl, cyanophenyl, tetrahydrobenzofuran, benzopyran,dihydrobenzodioxin, benzoxazinone, benzooxadiazole, benzodioxole,indoline, and benzomorpholine.
 6. A compound according to claim 2wherein: R₃ is H, F or CH₃, preferably R₃ is H or F.
 7. A compoundaccording to any one of the preceding claims wherein: R₄ is preferablyselected from the group consisting of hydrogen, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted acyl, optionally substitutedarylalkyl, and optionally substituted heteroaryl, preferred examples arehydrogen, methyl, ethyl, propyl, isopropyl and 2-hydroxyethyl.
 8. Acompound according to any one of the preceding claims wherein: R₅ and R₆are optionally substituted alkyl; and preferably, R₅ and R₆ are CH₃. 9.A compound according to any one of the preceding claims where A is achemical moiety of Formula (VIII);

Wherein; R₂ is selected from compounds of formula (IV), (V) (VI) or(VII), and R₉, R₁₀, R₁₁, R₁₂ and R₁₃ are defined as above.
 10. Acompound according to any one of the preceding claims where formula (I)is represented by (IX), (X), (XII)

Wherein; A is a chemical moiety of formula (VIII), and R₃ and R₄ are asdefined in claim 6 and claim 7 respectively.
 11. A compound according toany one of the preceding claims selected from:1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amidePyridine-3-sulfonic acid(40chloro-benzyl)-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-amideN-(4-Chloro-benzyl)-3-cyano-N-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-amidePyridine-3-sulfonic acid(4-chloro-benzyl)-[2-(2-hydroxy-ethyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amideN-(4-Chloro-benzyl)-3-cyano-N-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(2-methyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-[2-(2-hydroxy-ethyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amideN-(4-Chloro-benzyl)-3-cyano-n-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamideN-(4-Chloro-benzyl)-3-cyano-N-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)benzene sulfonamide Pyridine-3-sulfonic acid(4-chloro-benzyl)-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-5-yl)-amidePyridine-3-sulfonic acid94-chloro-benzyl)-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-isopropyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-amide1-Methyl-1H-pyrazole-3-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-amide1-Methyl-1H-pyrazole-3-sulfonic acid benzyl(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amide1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-amide1-Methyl-1H-imidazole-4-sulfonic acid(4-chloro-benzyl)-(2-ethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-amide1-Methyl-1H-imidazole-4-sulfonic acidbenzyl-(2-ethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide.
 12. Apharmaceutical composition comprising at least one compound as claimedin any one of claims 1 to 11 optionally together with one or morepharmaceutically acceptable excipients, diluents and/or carriers.
 13. Acompound as claimed in any one of claims 1 to 12 for use in medicine.14. A compound according to claim 13 for use in the prevention ortreatment of a disorder which requires potassium channel inhibition. 15.A compound according to claim 14 wherein said disorder is psoriasis,rheumatoid arthritis, multiple sclerosis or other immunologicaldisorders.
 16. A method as claimed in claim 14 wherein the disorder isarrhythmia.
 17. A method for the prevention or treatment of a disorderwhich requires potassium channel inhibition, comprising administering toa subject an effective amount of at least one compound formulas definedin any one of claims 1 to 11 or a pharmaceutical composition as definedin claim
 12. 18. A method as claimed in claim 17 wherein the disorder ispsoriasis, rheumatoid arthritis, multiple sclerosis or otherimmunological disorders.
 19. The use of a compound as defined in any oneof claims 1 to 11 in the manufacture of a medicament for use inpotassium channel inhibition.
 20. The use as claimed in claim 19 whereinthe medicament is for use in the treatment of psoriasis, rheumatoidarthritis, multiple sclerosis or other immunological disorders.